Special Feature

Pediatric Kidney Disease: Tracking Onset and

Improving Clinical Outcomes
Carlton M. Bates, Jennifer R. Charlton, Maria E. Ferris, Friedhelm Hildebrandt, Deborah K. Hoshizaki,
Bradley A. Warady, and Marva M. Moxey-Mims, on behalf of the Kidney Research National Dialogue

Abstract
Recent studies confirm that much of adult kidney disease may have its origins in childhood, often as a result of
Due to the number of
abnormal or suboptimal fetal kidney development. Understanding of the etiology and pathogenesis of CKD in
contributing authors,
children is rapidly evolving because of robust longitudinal clinical data, identification of monogenic mutations the affiliations are
related to common causes of CKD, and improved knowledge of factors that influence the onset and progression provided in the
of CKD. The Kidney Research National Dialogue, supported by the National Institute of Diabetes and Digestive Supplemental
and Kidney Diseases, asked the research and clinical communities to formulate and prioritize research objectives Material.
that would improve understanding of kidney function and diseases. This commentary outlines high-priority
Correspondence:
research objectives to assess factors associated with the predisposition to develop renal disease in children, and
Dr. Marva M. Moxey-
address the unique challenges in treating this population. Mims, Division of
Clin J Am Soc Nephrol 9: 1141–1143, 2014. doi: 10.2215/CJN.00860114 Kidney, Urologic, and
Hematologic
Diseases, National
Institute of Diabetes
Introduction providing valuable clinical data detailing risk factors and Digestive and
Kidney Diseases,
The National Institute of Diabetes and Digestive and for CKD progression and its associated complications. National Institutes of
Kidney Diseases asked the community to identify These findings will expand our understanding of dis- Health, 6707
research objectives that, if addressed, would improve ease mechanisms and improve genetic counseling, etio- Democracy
our understanding of basic kidney function and aid logic classification for clinical trials, and screening for Boulevard, Room 639,
in the prevention, treatment, or reversal of kidney Bethesda, MD 20892.
potential therapeutic agents.
Email: mm726k@nih.
disease. Through the Kidney Research National Di- Below are the areas of investigation proposed through gov
alogue (KRND), .1600 participants posted .300 re- the KRND process.
search objectives covering all areas of kidney disease.
This commentary focuses specifically on opportunities
to advance the knowledge of factors related to the Research Objectives
onset and progression of pediatric kidney diseases, 1. Find Genetic and Environmental Factors That Affect
as well as the diagnostic and treatment-related events Prenatal Kidney Development
that occur over a child’s life course (Figure 1). Animal studies have revealed many genetic and
In the first 2 decades of life, congenital anomalies of some environmental causes of CAKUT. Despite recent
the kidneys and urinary tract (CAKUT), nephrotic studies that validate the role of these insults in human
syndrome, and renal cystic ciliopathies are responsi- cases of kidney and/or urinary tract maldevelopment
ble for 45%, 15%, and 5% of CKD cases, respectively, (1), as well as the recent successes in the identification
on the basis of data from the North American of causal genes of CAKUT via high-throughput se-
Pediatric Renal Trials and Collaborative Studies. quencing, the majority of the causes of human CAKUT
Many factors influence the onset and progression of remain unclear. The emerging number of repositories
pediatric kidney diseases, as well as the diagnostic with biosamples from pediatric populations offers the
and treatment-related events that occur over a child’s possibility of finding novel causes of CAKUT. In addi-
life course (Figure 1). Genetic factors likely interact tion, advances in our knowledge of the underlying
with the prenatal environment to cause developmen- mechanisms regulating the establishment, mainte-
tal abnormalities, intrauterine growth restriction, and nance, and differentiation of murine renal progenitor
premature birth. Both the development of CAKUT cells has led to paradigms for manipulating nephron
and abridged renal development seen with prematu- number and determinants of kidney endowment.
rity compromise the final functional renal mass. Patient-oriented, translational studies have estab-
Hence, low nephron number might predispose the lished associations of low birth weight and premature
child to later disease as a result of insufficient renal birth with reduced nephron number and predisposition
reserve. The rate of CKD progression is also affected toward renal disease. Robust studies of the antenatal and
by clinical exposure to AKI, hypertension, obesity, perinatal environments and their relationship to impor-
and diabetes mellitus. Studies such as the Chronic tant long-term outcomes are needed. The fetal response
Kidney Disease in Children (CKiD) cohort study are to extreme maternal undernutrition can be traced in

www.cjasn.org Vol 9 June, 2014 Copyright © 2014 by the American Society of Nephrology 1141
1142 Clinical Journal of the American Society of Nephrology
Figure 1. | Life course of pediatric-onset CKD. This timeline shows progression of pediatric-onset kidney disease from aberrant prenatal
development, through insults to the kidney during childhood and on into adulthood. The effect of both clinical and lifestyle exposures is shown.
The lower panel shows the high-priority research objectives needed to improve outcomes at different points in the life course. CAKUT, con-
genital anomalies of the kidneys and urinary tract.
studies based on the Dutch famine and have revealed the
persistence of epigenetic markers of key genes involved in
growth and development. Thus, advances in understanding the
fetal response to undernutrition in model organisms that focus
on nephron number, perhaps in concordance with clinical
studies (e.g., CKiD), would increase knowledge pertaining to
the control of nephron endowment and functional renal mass.
It is thought that nephron number is determined at the time of
birth with no known capacity for nephron regeneration. Test-
ing whether low nephron number contributes to the develop-
ment of kidney disease is stymied by the lack of noninvasive
ways to quantify nephron number/function and fibrosis in
humans. However, newer techniques, such as magnetic reso-
nance imaging detection of charged ferritin binding to glomer-
ular basement membrane or diffusion tensor imaging, might
allow repeated assessments to provide insight into the devel-
opment of progressive kidney disease or measurement of neph-
ron regeneration, and might aid the design of therapies to halt
CKD advancement. These efforts will require close collabora-
tion between pediatric nephrologists, maternal-fetal medicine
specialists, neonatologists, and developmental biologists.
2. Identify Genetic Causes of Pediatric CKD
The number of known causative genes contributing to the
pathogenesis of pediatric CKD in children is growing, and
additional investigative efforts are likely to reveal an increased
fraction of cases with an identifiable monogenic cause of CKD.
These findings will have major implications for the diagnosis
and treatment of early-onset CKD. Not only will detection of
the causative mutations provide an unequivocal diagnosis, but
this may prove to be an important determinant of outcome. In
addition, the determination of causative genes will inform our
understanding of pathogenesis and enable the generation of
gene-specific animal models to conduct high-throughput
drug screening.
3. Understand AKI in Neonates
The potential to reduce the morbidity, mortality, and cost of
care for neonates depends on our ability not only to accurately
diagnose AKI, but also to define patient characteristics, improve
our general epidemiologic and ecologic understanding of risk
factors, and determine the optimal time and methods for in-
tervention. Over the last several years, accumulating evidence
supports the connection between AKI and CKD in both the
adult and pediatric populations (2,3). Whereas standard defi-
nitions of adult AKI are improving, the definition of neonatal
AKI, particularly for the premature neonate, is confounded by
both the natural changes in newborn GFR and the ability to
secrete creatinine in an immature tubule. Unlike in adults, the
long-term effects of neonatal AKI have not been rigorously
studied. There is potentially a larger mismatch of nephron re-
serve and lifespan in the infant who has suffered AKI com-
pared with an adult who has suffered AKI. While neonatal AKI
can be stratified in many ways (due to asphyxia, nephrotoxins,
nephron immaturity, or congenital cardiac disease), it is impor-
tant to understand the biologic or physiologic influences in
each subpopulation so that therapies, interventions, and ongo-
ing follow-up are appropriately focused.
Multicenter collaborative efforts between pediatric nephrol-
ogy and neonatology will be required, given the relatively
small numbers of affected neonates at individual sites.
4. Develop Predictive Tools and Specific Treatments for
Pediatric Kidney Disease
As genetic mutations and predispositions are known, it
may be possible to specifically target different pathways in
Clin J Am Soc Nephrol 9: 1141–1143, June, 2014
children, rather than extrapolate from adult studies. There
is a need for predictive tools to assess the likelihood of pre-
disposition for renal disease. Recent studies have revealed a
wealth of biologic molecules and cells within the urine that
could be harnessed as predictive tools. Systematic analysis to
determine the transcriptome, proteome, and metabolome of
urine from prospective trials or studies, such as CKiD or the
Randomized Intervention for Vesicoureteral Reflux, might
provide such tools.
In addition, drugs are metabolized differently in infants
and children; thus, studies are needed to determine how to
tailor medication use in pediatric populations with CKD.
Pharmacokinetic studies as well as clinical studies that in-
corporate pharmacogenomic and pharmacometabolomic
data should help to “personalize” therapies with a goal of
increasing drug efficacy and minimizing toxicity.
5. Improve Treatment Adherence
The effect of nonadherence on healthcare costs and mor-
bidity is substantial. Adolescents are known to exhibit a high
degree of nonadherence, putting them at risk for accelerated
disease progression, in addition to renal allograft loss in the
transplant population. Although biomarkers of adherence are
available for people who receive immune-modulators, the
definition of nonadherence has not been agreed upon by
CKD/ESRD researchers. Further study is needed to better
understand risk factors for nonadherence, especially those that
are potentially modifiable. On the basis of current knowledge
of this long-standing clinical challenge, and with the ubiq-
uitous use of electronics and social media for communication
in this age group, the development of a multifaceted platform
of interventions aiming to improve adherence is warranted.
This could incorporate peer interactions in addition to any
“outside” efforts from medical caregivers and parents. Stud-
ies could be structured to test whether the implementation
and utilization of social media platforms, specifically tailored
to the needs of the individual, might improve adherence and
health outcomes in the adolescent population.
6. Enhance Self-Management and Healthcare Transition
from Child to Adult
To improve the health outcomes of adolescents and
emerging adults with CKD/ESRD as they transfer to adult-
focused health services, self-management and healthcare
transition preparation is critical and cost-effective (4). This
preparation from parent-directed care to disease self-
management should be planned and monitored longitudinally,
with the participation of the youth, caregiver, and interdisci-
plinary health providers from both child- and adult-focused
practices (5). A life course approach needs to be developed
and embraced in both pediatric and adult practices, imple-
menting patient/caregiver education programs that are cul-
turally and literacy-level appropriate. Innovative approaches
are needed to characterize specific population and sex-based
challenges to effective transitioning of adolescents to adult
care. Most importantly, the definition of successful healthcare
transition outcomes, tools to diagnose and measure health-
care transition preparation and implementation, and models
to guide interventions need to be developed and validated.
Although understanding health outcomes for children is
important, new initiatives designed to train pediatric and
Pediatric-Onset Kidney Disease, Bates et al. 1143
adult nephrology providers (along with primary care and
family medicine providers) how to care for those with
congenital and childhood-acquired kidney disease are vital.
Evidence-based curricula on developmentally appropriate
care for survivors of pediatric-onset CKD/ESRD will
need to pay particular attention to disease etiology, per-
centage of life with the disease, and medical/psychologic
comorbidities.
Conclusion
Although our understanding of pediatric-onset kidney
disease is improving, some key steps are needed to make
strides in therapy and self-management. These include a
better understanding of the underlying genetic and ma-
ternal environmental effects contributing to a predisposi-
tion toward CKD and an appreciation that the neonatal/
pediatric kidney is not the same as an adult kidney and,
thus, better disease definitions for the pediatric patient
are required. The latter should lead to the development
of pediatric-specific therapies, including targeted med-
ications. In addition, this population would benefit from
strategies to improve treatment adherence and training
of the medical workforce in a life course approach to
care.
Acknowledgments
The Kidney Research National Dialogue was developed and im-
plemented by the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) Division of Kidney, Urologic, and Hemato-
logic Diseases staff and directed by Dr. Krystyna Rys-Sikora. The Pe-
diatric topic was facilitated by Drs. M.M.M-.M. and D.K.H. The complete
listing of areas of research emphasis, in priority order, is available on the
NIDDK KRND webpage (http://www.niddk.nih.gov/about-niddk/
offices-divisions/division-kidney-urologic-hematologic-diseases/
kidney-research-national-dialogue/Pages/kidney-research-national-
dialogue.aspx). Please visit this website for updates on KRND.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
This article contains supplemental material online at http://cjasn.
asnjournals.org/lookup/suppl/doi:10.2215/CJN.00860114/-/
DCSupplemental.